The Epidermal Growth Factor Receptor (EGFR; HER1) is widely expressed in the kidney, and previous studies have suggested roles for receptor activation in nephrogenesis, regulation of renal physiology and in aberrant growth in renal cell cancer and polycystic kidney disease. Studies by our laboratory and others have implicated EGFR activation in recovery of renal tubule epithelia from acute injury. In addition, recent studies by us and others have also implicated EGFR activation in development of tubulointersitial fibrosis in chronic kidney disease. We propose that in both acute and chronic renal injury, EGFR activation is a necessary step for partial epithelial-mesenchymal transition; during recovery from ischemic injury, such dedifferentiation is necessary for the spreading, migration and proliferation, which are also mediated in part by EGFR, while persistent EGFR activation can lead to tubulointerstitial injury. We will investigate the role of EGFR activation during acute injury, mechanisms by which the receptor is activated and potential factors activated by EGFR that promote cell survival, dedifferentiation and proliferation. We have also elucidated a novel mechanism of persistent EGFR transactivation during chronic conditions leading to progressive tubulointerstitial fibrosis and will investigate the role and mechanism of chronic EGFR activation in this process. In addition, our studies during the current funding period have indicated that the membrane-associated form of EGFR ligands, and specifically heparin-binding EGF-like growth factor (HB-EGF), subserves different functions than the soluble mature form of the ligands and helps to maintain epithelial cell polarity, integrity and differentiation. We propose that these cellular responses mediated by the membrane-associated form of HB-EGF (proHB-EGF) occur both by juxtacrine signaling through EGFR and by serving as a scaffold for membrane-associated and cytoskeletal elements that promote cell-cell interactions. Therefore, cleavage of EGFR ligands can lead to cell activation by release of the soluble ligands, which can serve as autocrine and paracrine growth factors, as well as by disruption of cell-cell, cell-ECM and cytoskeletal interactions that then predispose the epithelial cells to motility, proliferation and dedifferentiation. There are three specific aims. Aim #1 will examine the role of EGFR activation in recovery from acute ischemic renal injury and will examine mechanisms of EGFR activation and potential downstream targets. Aim #2 will examine the role of persistent EGFR activation in the development of tubulointerstitial fibrosis and will investigate abnormalities in EGFR trafficking that mediate the persistent receptor activation. Aim #3 will examine the role of membrane-associated EGFR ligands in the maintenance and cytoprotection of renal epithelial cells. PUBLIC HEALTH RELEVANCE: Our studies indicate that both recovery from acute kidney injury and development of progressive renal tubulointerstitial injury are mediated in part by activation of the EGF receptor (EGFR). The proposed studies will examine the mechanisms by which EGFR is activated in both acute and chronic injury and the role and mechanisms in cytoprotection and tubule regeneration with acute injury and progressive tubulointerstitial damage resulting from chronic injury.